In the frustrating 40-year effort to develop a vaccine for HIV/AIDS, hardworking scientists could certainly use some help.
Newly published research suggests they may have found some in the form of a common white blood cell called a CD4 T lymphocyte — also known, incidentally, as a helper T cell.
A critical component of the human immune system, helper T cells also happen to be a primary target of HIV. When the virus erodes the level of these protective T cells to a critically low point, a person becomes vulnerable to lethal infections — developing AIDS.
Yet new research published today in the journal Science Translational Medicine shows that helper T cells could play a crucial role in a bold and complex new strategy for making an effective HIV/AIDS vaccine.
The study, carried out by the laboratory of Julie McElrath, MD, PhD, senior vice president and director of Fred Hutchinson Cancer Center’s Vaccine and Infectious Disease Division, is a deep analysis of T-cell responses to an experimental vaccine developed by Scripps Research, of La Jolla, California.
Renowned for its expertise in analyzing immune responses to vaccines and viruses, the McElrath lab frequently conducts such research for the Fred Hutch-based HIV Vaccine Trials Network, the world’s largest publicly funded collaboration to evaluate HIV/AIDS vaccines. Her lab is also sought out for its analytical expertise by vaccine developers at the National Institute of Allergy and Infectious Diseases, vaccine makers, and other academic centers carrying out such work.
Led by Scripps vaccine designer William Shief, PhD, his California-based group is one of several different teams around the world developing next generation HIV vaccines that rely on an approach called germline-targeting. The goal of that strategy is to coax the immune system, through a series of stepwise vaccinations, to produce so-called broadly neutralizing antibodies, or bnAbs, which are much harder for constantly mutating, shape-shifting HIV to slip free of.
While these bnAbs have the potential to stop HIV infection, they are not made readily by the human immune system and they cannot be generated yet by any conventional vaccine. The body essentially needs to be trained to make them, which is what germline targeting is all about.
In December, Shief and his collaborators published the first results of a small trial of 36 volunteers who received the first vaccine in what is envisioned to be a series of injections using several different immune stimulating “antigens” that will sequentially guide the body into making powerful bnAbs against HIV.
Shief’s paper focused on whether his experimental vaccine induced production of certain B cells, the immune system’s antibody making factories. In this case, the goal was to produce a class of “precursor” B cells that would be pushed closer to making the desired bnAbs in a follow-up sequence of different vaccines.
The December paper reported that 97% of the participants generated the sought-after precursor B cells. In fact, about 1 in every 1,000 B cells found in circulating blood of those participants was found to be that essential precursor cell. In that study, the McElrath laboratory contributed the analysis of how well that first vaccine generated the desired class of antibody.
In the newest paper, the McElrath lab takes center stage in an analysis of how that same Scripps vaccine stimulated not B cells, but T cells. The results were equally encouraging. Her lab found that the vaccine generated a “robust” response of CD4 cells, quickly accounting for about 5 of every 1,000 CD4 cells found in circulating blood. It worked just as well at a low dose of 20mcg as did a high dose of 100mcg per shot.
“We were quite encouraged that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine,” said McElrath, who holds the Joel D. Meyers Endowed Chair. “These results demonstrate the vast potential of this new approach of training the immune system to produce broadly neutralizing antibodies against HIV.”
The researchers note that the high level of CD4 production in this HIV vaccine study is as good or better than that found in tests of COVID-19 vaccines, which of course were proven to be highly effective. Although the HIV and COVID-19 vaccines are entirely different and target different diseases, evidence of a robust response is potentially good news.
So, if the goal of the germline strategy is to get B cells to eventually produce the right antibodies, why are T cells important?
Stephen De Rosa, MD, who helps direct the McElrath lab and is a co-lead author of the newest study, explains that CD4 cells may be essential for the germline strategy to develop an effective HIV vaccine because of their “helper” function.
If B cells are the factories that make antibodies, T cells operate a bit like factory floor managers. They are biological meddlers that communicate to other parts of the immune system, to rev up production of a variety of immune defenses that can block pathogens, kill them, or kill our own cells that have become infected. They like to tell B cells what to do.
“B cells don’t work on their own, at least during development of the immune response. They require help from T cells. That’s the key point,” De Rosa said.
— Dr. Julie McElrath, senior vice president and director of Fred Hutch's Vaccine and Infectious Disease Division
The goal of the germline strategy is to nudge, or fine-tune the evolution of ordinary B cells into ones that can make bnAbs. T cells help that process by assuring that the precursor B cells survive, multiply, and mutate into the desired form. The latter process, called somatic hypermutation, is a fundamental tool and the CD4 cells provide critical assistance to guide this evolution of B cells.
The latest paper on the T cell response had a number of encouraging observations that vaccine developers want to see. For example, the McElrath lab found that most CD4 cells stimulated by the vaccine produced a number of biological signals, what biologists call polyfunctionality. Most often, they produced a quartet of common but important chemicals that are involved in the complex communication of commands among immune cells: interferon-gamma, interleukin-2, tumor necrosis factor, and a protein marker called CD40L.
In one unexpected finding, the vaccine appears to stimulate not only CD4 helper T cells, but another flavor of T cell, CD8s, which are nicknamed “killer” cells because their primary job is to poison or destroy cells recognized as foreign or diseased. It is conceivable that a fired up contingent of CD8 cells could serve as a backstop to kill any cells that are infected by HIV virions that somehow escape the protection put up by broadly neutralizing antibodies.
Although researchers cannot be sure, it appears that the successful rousing of T cells may be linked to the design of the vaccine, dubbed eOD-GT8. Scientist might not like the analogy, but a microscopic view of the EOD structure would show something resembling the head of a round toilet brush. Each spherical “nanoparticle” bristles with 60 copies of an antigen — a protein found on the surface of HIV chosen as a target for antibodies. These individual bristles are attached to a base derived from an enzyme found in a bacteria. The analysis found that the T cells responded strongly to both the brushes and the base of this unique vaccine particle — findings that suggest this structure, particularly the base, might be a useful one for the design of vaccines to prevent other diseases.
De Rosa explains that bnAbs were an unexpected discovery in HIV research. The first were detected in 1990, in the blood of HIV patients who had long, persistent infections. The bnAbs taken from the blood of these patients were produced over time by a natural process of hypermutation. So, the essence of the germline strategy is to imitate the natural process that produced bnAbs and use it — through that succession of cleverly designed vaccines — to get the bodies of healthy, uninfected people to protect them from infection.
He believes the mutational nudges of T cells might be central to making that strategy work. In his view, one family of broadly neutralizing antibodies will probably not succeed. It may require a “cocktail” of three different bnAb families, induced by a sequence of germline targeted vaccines, to do the trick.
To be clear, the immune cells and the antibodies produced in this early test of the germline strategy are not able to neutralize HIV. The purpose of the first injections is to prime the immune system for several further steps that will force these precursor B cells to evolve closer and closer to B cells that can make broadly neutralizing antibodies.
The experiment is an example of a new approach to HIV vaccine development, in the wake of the failures of once promising candidates. The idea is that, instead of mustering large trials of vaccine candidates primed for manufacture by drug companies, researchers will conduct many smaller, faster trials to assess whether a new vaccine concept might work. Scientists call these discovery medicine trials. The hope is that these small, intensively analyzed studies, will lead to a faster acceptance or rejection of path to HIV vaccine development.
The vaccine work outlined in these two papers now sets the stage for future discovery medicine trials that will use at least two different antigens to nudge those precursor B cells a little closer to bnAbs. Shief calls the first step “priming” the immune system and the second step “shepherding.”
If that shepherding study is as successful as the first, the vaccine developers envision a final injection of another antigen that will produce the desired broadly neutralizing antibody. The researchers call that final step “polishing.”
From priming to shepherding to polishing, T cells may be just the help researchers need to get B cells to make bnAbs.
“This whole concept in terms of shepherding a response falls on the side of B cells that need T cell help,” De Rosa said. “One of the primary roles of T cell help is that they are very important for assisting B cells in attaining those mutations.”
The Scripps Research study is sponsored by IAVI, a nonprofit scientific research organization headquartered in New York. The McElrath lab work was funded by the Bill & Melinda Gates Foundation.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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